Many psychiatric illnesses lead to alterations in mood, perception and memory. How activity in the brain leads to accurate perception and memory recall is a critical basic question in neuroscience that has been difficult to address directly. In this grant we develop an approach in mice that allows the genetic alteration of neurons based on their activity in response to a natural environmental stimulus or learning paradigm. We use this to introduce either the hM3Dq DREADD receptor or a variant of channelrhodopsin (ChEF) to allow the electrical stimulation of the labeled neurons either chemically or with light. In this way we can directly stimulate the ensemble of neurons activated naturally in response to a stimulus in the behaving animal to investigate the parameters required to produce a perception or memory. In preliminary studies we show that anatomically dispersed, and internally generated neural activity can be integrated into new memory. This is consistent with the idea that new memory does not form de novo but integrates with pre-existing schemas or relevant internal representations that may be active at the time of learning. Using ChEF we found that light stimulation of neurons in the retrosplenial cortex that were activated naturally with fear conditioning could produce a freezing response. This suggests that we are directly recruiting a component of the memory trace through the artificial stimulation of the correct pattern of neurons. We will extend these studies to investigate the parameters that control the integration of neural activity into new and existing memories during consolidation and reconsolidation. In addition, we will use local stimulation to directly test the optimal conditions (number of neurons, firing frequency) required for recruiting memory recall. These studies will provide the first direct test of the role of spatial and temporal patterns of neural activity in th generation of perceptions and memories. The data generated should advance our understanding of psychiatric disorders and aid in the creation of animal models in which to test treatments.